Iridium-Catalyzed Asymmetric Hydrogenation of Tosylamido-Substituted Pyrazines for Constructing Chiral Tetrahydropyrazines with an Amidine Skelton

Article abstract of DOI:10.1002/adsc.201600852

Dinuclear triply chloro-bridged iridium(III) complexes bearing chiral diphosphine ligands catalyze the asymmetric hydrogenation of tosylamido-substituted pyrazines to give the corresponding chiral tetrahydropyrazines with an amidine skeleton in high yield and with high enantioselectivity. Addition of N,N-dimethylanilinium bromide enhanced the catalytic activity of the iridium complexes and also increased the enantioselectivity of the products by trapping the hydrogenated amine products with HBr from N,N-dimethylanilinium bromide. The amidine skeleton of the products could be transformed to give chiral piperazinones and piperazines without loss of enantioselectivity. (Figure presented.).

Full text of DOI:10.1002/adsc.201600852

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DOI: 10.1002/adsc.201600852
Iridium-Catalyzed Asymmetric Hydrogenation of Tosylamido-
Substituted Pyrazines for Constructing Chiral Tetrahydropyra-
zines with an Amidine Skelton
Kosuke Higashida,a Haruki Nagae,a and Kazushi Mashimaa,*
a
Department of Chemistry, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka 560–8531, Japan
Fax : (+81)-6-6850-6249; phone: (+81)-6-6850-6248; e-mail: mashima@chem.es.osaka-u.ac.jp
Received: August 1, 2016; Revised: October 13, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600852.
Abstract: Dinuclear triply chloro-bridged iridiu-
m(III) complexes bearing chiral diphosphine li-
gands catalyze the asymmetric hydrogenation of to-
sylamido-substituted pyrazines to give the corre-
sponding chiral tetrahydropyrazines with an ami-
dine skeleton in high yield and with high enantiose-
lectivity. Addition of N,N-dimethylanilinium
bromide enhanced the catalytic activity of the iridi-
um complexes and also increased the enantioselec-
tivity of the products by trapping the hydrogenated
amine products with HBr from N,N-dimethylanilini-
um bromide. The amidine skeleton of the products
could be transformed to give chiral piperazinones
and piperazines without loss of enantioselectivity.
ieved in high yield and with high enantioselectivity.
Asymmetric hydrogenation of pyrazines to afford the
corresponding chiral piperazines, however, is consid-
ered more difficult than hydrogenation of the afore-
mentioned N-heteroaromatics due not only to the ar-
omatic stabilization of pyrazines, but also to the high
coordination ability of pyrazines and piperazines.
Pioneering work was accomplished by Fuchs who
used rhodium complexes bearing chiral diphosphine
ligands for the asymmetric hydrogenation of amide-
substituted pyrazines to give the corresponding chiral
amide-substituted piperazines with moderate enantio-
selectivity.[12] Recently, chiral iridium complexes were
successfully applied to the asymmetric hydrogenation
of pyrazinium units of the pyrrolo[1,2-a]pyrazinium
salts, composed of a pyrrole ring fused to a pyrazinium
salt ring,[13] and, quite recently, a chiral iridium cata-
lyst under lower temperature (À208C) was reported
to catalyze the asymmetric hydrogenation of N-ben-
zylpyrazinium salts (Scheme 1).[14,15]
Keywords: asymmetric hydrogenation; chiral tetra-
hydropyrazines; iridium catalyst; piperazines; piper-
azinones; pyrazines
We have developed halide-bridged dinuclear com-
plexes of iridium(III) and rhodium(III) bearing chiral
Chiral piperazines and their derivatives, among the diphosphine ligands to reduce various N-heteroaro-
most common chiral six-membered cyclic amines, are matic compounds and simple olefins, respectively.[9,16]
abundant in natural products and bioactive com- Notably, for the asymmetric hydrogenation of N-het-
pounds (Figure 1).[1] To prepare the chiral piperazines,
intensive investigations were devoted to developing
various synthetic protocols, including two component
cyclization,[2] enantioselective addition of organome-
tallic reagents supported by chiral amines,[3] and opti-
cal resolution.[4] These reactions require stoichiomet-
ric amounts of chiral compounds or multistep reac-
tions, however, and thus more practical and straight-
forward synthetic methods are in high demand.
Asymmetric hydrogenation of N-heteroaromatic
compounds provides a rational synthetic tool for con-
structing chiral cyclic amines: asymmetric hydrogena-
tion of various N-heteroaromatic compounds,[5] such
as quinoline,[6] isoquinoline,[7] quinoxaline,[8] quinazo-
Figure 1. Some examples of bioactive compounds comprised
line,[9] pyridine,[10] and pyrimidine,[11] have been ach- of chiral piperazine derivatives.
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Table 1. Screening of catalysts.
Entry
Catalyst
Yield [%][a]
ee [%][b]
1[c]
2
3
4
5
6
7
8
(S)-1a
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
(S)-1f
(S)-1g
23
55
34
57
53
7
47
73
55
72
70
4
trace
43
not determined
83
[a]
1
Determined by H NMR analysis using triphenylmethane
as an internal standard.
[b]
[c]
Determined by HPLC analysis.
Reaction was performed without lutidinium chloride.
with the iridium center. In fact, we had successfully
applied such a salt formation strategy to reduce iso-
quinolinium salts,[16d,e] quinazolinium salts,[9] and pyri-
dinium salts[16c] by adding stoichiometric amounts of
Scheme 1. Asymmetric hydrogenation of pyrazines reported
so far.
eroaromatic compounds, the use of the HX salt for- lutidinium chloride as a source of HCl to trap the hy-
mation of N-heteroaromatic compounds as substrates drogenated product 3a in situ,[17] because 2a did not
dramatically improved both the catalytic reactivity produce its HCl salt due to its low basicity and luti-
and the enantioselectivity. In this communication, we dine was not hydrogenated under the catalytic condi-
report that dinuclear chloride-bridged iridium(III) tions.[18] Thus, we conducted the asymmetric hydroge-
complexes 1a–g (Figure 2) worked as catalysts for the nation of 2a in the presence of lutidinium chloride
asymmetric hydrogenation of 2-tosylamido-5-substi- (1.2 equiv.) to give the product (S)-3a in 55% yield
tuted pyrazines upon combination with stoichiometric and 73% ee (entry 2). In the presence of lutidinium
amounts of the HBr salt of N,N-dimethylaniline as an chloride (1.2 equiv.), we screened for the best catalyst,
additive, producing the corresponding chiral amidinat- and the results are summarized in Table 1. Iridium
ed tetrahydropyrazines in high yield and high enantio- complex (S)-1b bearing (S)-tol-BINAP showed less
selectivity, which were versatile precursors for chiral activity and low enantioselectivity (entry 3), while iri-
piperazine derivatives.
We initiated the asymmetric hydrogenation of 4- PHOS and (S)-SEGPHOS, respectively, afforded (S)-
methyl-N-(5-phenylpyrazin-2-yl)benzenesulfonamide 3a in almost the same yield (53–57%) and with enan-
dium complexes (S)-1c and (S)-1d bearing (S)-SYN-
(2a) in 1,4-dioxane under hydrogen gas (30 bar) using tioselectivity (70–72%) (entries 4 and 5). When com-
(S)-1a, which resulted in very low catalytic activity plexes (S)-1e and (S)-1f with much bulkier ligands
(Table 1, entry 1). To improve the catalytic per- were used as catalysts, hydrogenation did not proceed
formance, salt formation of N-heteroaromatic com- smoothly (entries 6 and 7). Finally, complex (S)-1g in-
pounds with Brønsted acids was strategically applied creased enantioselectivity (83%) although with a low
to trap the amine products that strongly coordinated yield (43%) of (S)-3a, and thus (S)-1g was selected as
the best catalyst in terms of high enantioselectivity
(entry 8).
With the best iridium catalyst in hand, we next ex-
amined salt additives, and the results are shown in
Table 2. Among the salts of lutidine, such as lutidini-
um chloride, bromide, iodide, pentafluorobenzoate,
and tosylate, the HBr salt of lutidine gave (S)-3a with
the highest enantioselectivity (entries 1–5), and then
we searched for various HBr salts of amines. Using
Figure 2. Dinuclear iridium(III) complexes used as catalysts. 2,6-(t-Bu)2pyridine as the bulky base, enantioselectivi-
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Table 2. Screening of additives.
Table 3. Scope and limitations.
Yield [%][a] ee [%][b]
Entry
R
Yield [%][a]
ee [%][b]
Entry Additive
1
2
3
4
5
6
7
8
p-MeOC6H4
p-CF3C6H4
p-CO2MeC6H4
m-MeOC6H4
m-CF3C6H4
o-MeC6H4
2b
2c
2d
2e
2f
2g
2h
2i
98
76
91
98
76
98
96
94
92 (+)
78 (+)
91 (+)
90 (+)
82 (+)
79 (+)
86 (S)
84 (+)
1
2
3
4
5
6
7
8
lutidine·HCl
lutidine·HBr
lutidine·HI
lutidine·C6F5COOH
lutidine·TsOH
43
63
80
3
20
95
92
52
83
88
83
43
80
66
90
85
75
88
88
93
88
86
2,6-(t-Bu)2pyridine·HBr
aniline·HBr
cyclopentyl
n-hexyl
p-MeO-aniline·HBr
p-CF3-aniline·HBr
N-methylaniline·HBr
N,N-dimethylaniline·HBr
N,N-dimethylaniline·HBr
N,N-dimethylaniline·HCl
N,N-dimethylaniline·HI
9
98
97
[a]
Isolated yield.
10
11
12[c]
13[c]
14[c]
[b]
Determined by HPLC analysis.
DMA = N,N-dimethylaniline
>99
>99 (98)[d]
18
86
We applied the best conditions for various sub-
strates (Table 3). Asymmetric hydrogenation of p-me-
thoxy derivative 2b quantitatively yielded (+)-3b with
high enantioselectivity (92% ee) (entry 1), whereas in-
troduction of an electron-withdrawing group such as
CF3 at the p-position decreased both the yield and
enantioselectivity (entry 2). The ester group of 2d re-
mained intact under the reduction to give (+)-3d in
[a]
1
Determined by H NMR analysis using triphenylmethane
as an internal standard.
[b]
[c]
[d]
Determined by HPLC analysis.
Reaction was conducted at 308C.
Isolated yield.
ty was decreased to 66%, while (S)-3a was obtained 91% yield and 91% ee (entry 3). m-Methoxy-substi-
in 95% yield (entry 6). When anilinium bromide was tuted substrate 2e was hydrogenated smoothly to give
used as an additive, both the yield and enantioselec- (+)-3e in 90% ee (entry 4); however, asymmetric hy-
tivity were increased in comparison with those of the drogenation of m-trifluoromethyl-substituted sub-
reaction with lutidinium bromide, probably due to an strate 2f afforded only a moderate yield and enantio-
interaction of amines and iridium metal center selectivity as well as that of 2c (entry 5). A methyl
(entry 7).[16b,19] The electron-donating or electron- group at the m-position decreased enantioselectivity
withdrawing substituent on aniline, however, led to due to steric hindrance (entry 6). Alkyl-substituted
a decrease in the enantioselectivity (entries 8 and 9). pyrazines were the competent substrates to afford the
The addition of N-methylanilinium bromide and N,N- corresponding reductants, (S)-3h and (+)-3i, in high
dimethylanilinium bromide in the reaction mixture yield with moderately high enantioselectivity (en-
improved the yield of the (S)-3a to 97% and >99%, tries 7 and 8). On the other hand, asymmetric hydro-
respectively, with high enantioselectivity (entries 10 genation of 2-tosylamido-6-phenylpyrazine did not
and 11). We performed an asymmetric hydrogenation proceed under the same conditions,[20] probably due
of 2a at 308C with N,N-dimethylanilinium bromide, to the tight coordination of the substrate to the iridi-
and (S)-3a was isolated in 98% yield and 93% ee um center since the substrate had no substitution next
(entry 12). Finally, we further examined the halide ef- to the nitrogen atom at 4-position.[16g]
fects by testing N,N-dimethylanilinium chloride and
Scheme 2 shows the rational derivatization of (S)-
N,N-dimethylanilinium iodide, which resulted in 3a. Hydration of (S)-3a with saturated K2CO3 aque-
lower yield and enantioselectivity (entries 13 and 14). ous solution under 608C converted the tosylamide
Thus, it was rationalized that counter anions differen- group to a carbonyl group to afford (S)-4a in 91%
tiated enantioselectivity due to the six-membered yield with 92% ee. Reduction of (S)-3a with LiAlH4
transition state involving the counter anion and N–H in THF followed by treatment with Boc2O gave tert-
proton of the substrate salt.[15e] We therefore decided butyl (S)-3-phenylpiperazine-1-carboxylate [(S)-5a] in
that the optimized conditions required 2 mol% of (S)- 80% yield without loss of enantioselectivity.
1d and 1.2 equivalents of N,N-dimethylanilinium bro-
To gain insights into the reaction pathway, deutera-
mide in 1,4-dioxane under hydrogen gas (30 bar) at tion of 2a was conducted with deuterium gas (8 bar)
308C for 16 h.
and deuterium bromide salt as the deuterium sources
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methylanilinium bromide to give bromide salt III as
an intermediate. According to the deuterium labeling
experiment, an original hydrogen atom at the C-6 po-
sition was replaced with deuterium, suggesting tauto-
merization between enaminium III and iminium IV.
Additionally, because of the equal deuterium distribu-
tion at both hydrogens of the methylene at the C-6
position, a second reduction proceeded at the N-4=C-
5 bond of iminium IV to afford 3 as the resulting
product.
In summary, tosylamide-substituted pyrazines were
hydrogenated using dinuclear iridium(III) complexes
as catalysts to afford the corresponding chiral tetrahy-
dropyrazines bearing the amidine skeleton in high
yield and with high enantioselectivity. Additionally,
we demonstrated that the hydrogenated product, (S)-
3a, was readily transformed to the corresponding
chiral piperazinone and piperazine while maintaining
enantiopurity.
Scheme 2. Preparation of (S)-5-phenylpiperazin-2-one [(S)-
4a] and tert-butyl (S)-3-phenylpiperazine-1-carboxylate [(S)-
5a].
Experimental Section
General Procedure for Ir-Catalyzed Asymmetric
Hydrogenation of Pyrazine 2
Iridium complexes (2.4 mmol, 2.0 mol%), DMA·HBr
(0.144 mmol, 1.2 equiv.), and 4-methyl-N-(5-phenylpyrazin-
2-yl)benzenesulfonamide (2a) or its derivatives 2b–
i (0.12 mmol) were added to a glass tube in a reactor and
the tube was charged with argon. Dry 1,4-dioxane (3 mL)
was added to the glass tube in the reactor and charged with
H2, and the pressure was increased to the desired pressure.
The reaction mixture was stirred for 16 h at 308C. After re-
lease of H2, the reaction mixture was poured into a saturated
aqueous solution of NaHCO3 and extracted with DCM. The
organic layer was dried over Na2SO4. The filtrate was con-
centrated under vacuum, and the residue was purified by
column chromatography on silica gel (hexane/EtOAc=50/
50 to EtOAc) to afford the desired products.
Scheme 3. Deuterium labeling experiment.
(Scheme 3). The distribution of deuterium in the deu-
terated product ([D]-3a) was determined by H NMR,
1
which revealed that 49%, >95%, and 75% of the
deuterium was incorporated at the C-3, C-5, and C-6
positions, respectively. Based on these results, a plausi-
ble reaction pathway is proposed in Figure 3. Possible
tautomerization between sulfonamide 2 and sulfoni-
mide I was considered to promote dearomatization of
the starting material.[21,22] After an initial reduction at
the C-3=N-4 bond, amine II was trapped by N,N-di-
Preparation of pyrazine 2, general procedure for synthe-
sizing 4a and 5a, full characterization data and copies of rel-
evant spectra of all new products, and X-ray crystallographic
analysis data of 3h[23] are provided in the Supporting Infor-
mation.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Num-
bers JP26248028, a Grant-in-Aid for Scientific Research (A)
of The Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
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[18] Asymmetric hydrogenation of lutidinium chloride in
1,4-dioxane with 2 mol% of (S)-1g under 30 bar hydro-
gen gas at 608C for 16 h gave no reaction.
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[19] M. Renom-Carrasco, P. Gajewski, L. Pignataro, J. G.
de Vries, U. Piarulli, C. Gennari, L. Lefort, Chem. Eur.
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[20] Asymmetric hydrogenation of 2-tosylamido-6-phenyl-
pyrazine in 1,4-dioxane with 2 mol% of (S)-1g and
1.2 equivalents of DMA·HBr under 30 bar hydrogen
gas at 308C for 16 h did not proceed.
[21] a) S. O. Nilsson, A. Broo, Cryst. Growth Des. 2014, 14,
3704–3710; b) S. Ghosh, P. P. Bag, C. M. Reddy, Cryst.
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[22] Asymmetric hydrogenation of simple 2-phenylpyrazine
gave no reaction in 1,4-dioxane with 2 mol% of (S)-1g
and 1.2 equivalents of DMA·HBr under 30 bar hydro-
gen gas at 308C for 16 h gave no reaction.
[23] CCDC 1496586 (3h) contains the supplementary crys-
tallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
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Iridium-Catalyzed Asymmetric Hydrogenation of
Tosylamido-Substituted Pyrazines for Constructing Chiral
Tetrahydropyrazines with an Amidine Skelton
7
Adv. Synth. Catal. 2016, 358, 1 – 7
Kosuke Higashida, Haruki Nagae, Kazushi Mashima*
Adv. Synth. Catal. 0000, 000, 0 – 0
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ÞÞ
These are not the final page numbers!